Despite advances in
pharmacologic and nonpharmacologic management, N&V remain two of
the more distressing and feared side effects to cancer patients and their
families, and incidence may be underestimated by physicians and nurses.[1-5]

In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.

Introduction

Nausea is a subjective phenomenon of an unpleasant, wavelike sensation
experienced in the back of the throat and/or the epigastrium that may culminate in vomiting (emesis). Vomiting is the forceful expulsion of the contents
of the stomach, duodenum, or jejunum through the oral cavity. Retching is
gastric and esophageal movements of vomiting without expulsion of vomitus and
is also referred to as dry heaves.

Classifications

Various classifications of N&V have been used,[1,6]
including acute, delayed, late or persistent, chronic, anticipatory,
breakthrough, or refractory, as well as distinctions related to type of
treatment (e.g., chemotherapy induced or radiation induced) and clinical course of disease (e.g.,
advanced or terminal disease).[7,8] Despite this variety, the most commonly
described types of N&V are acute, delayed, and anticipatory chemotherapy-induced N&V
and chronic N&V in advanced cancer patients. Although there are no standard
definitions, the following are commonly used to classify the different types.

Acute N&V: N&V experienced during the first 24-hour
period after chemotherapy administration is considered acute N&V.[1]

Delayed (or late) N&V: N&V that occurs more than 24
hours after chemotherapy administration is considered delayed, or late, N&V.
Delayed N&V is associated with cisplatin, cyclophosphamide, and other drugs
(e.g., doxorubicin and ifosfamide) given at high doses or on 2 or more
consecutive days.

Anticipatory nausea and vomiting (ANV): ANV is nausea and/or vomiting that
occurs prior to the beginning of a new cycle of chemotherapy in response to
conditioned stimuli such as the smells, sights, and sounds of the treatment
room. ANV is a classically conditioned response that typically occurs after three
or four prior chemotherapy treatments, following which the person experienced
acute or delayed N&V.

Chronic N&V in advanced cancer patients: Chronic
N&V in the advanced cancer patient is N&V associated with a
variety of potential etiologies. A definitive understanding of cause is neither
well known nor well researched, but potential causal factors include
gastrointestinal, cranial, metabolic, drug-induced (e.g., morphine), cytotoxic
chemotherapy, and radiation-induced mechanisms.[9]

National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Bethesda, Md: U.S. Department of Health and Human Services, National Institutes of Health, 2010. Available online. Last accessed March 5, 2015.

Neurophysiology

Progress has been made in understanding the neurophysiologic mechanisms that
control nausea and vomiting (emesis) (N&V). Both are controlled or mediated by the central
nervous system but by different mechanisms. Nausea is mediated through the
autonomic nervous system. Vomiting results from the stimulation of a complex
reflex that is coordinated by a putative true vomiting center, which may be
located in the dorsolateral reticular formation near the medullary respiratory
centers. The vomiting center presumably receives convergent afferent
stimulation from several central neurologic pathways, including the
following:[1,2]

A chemoreceptor trigger zone (CTZ).

The cerebral cortex and the limbic system in response to sensory
stimulation (particularly smell and taste), psychologic distress, and pain.

The vestibular-labyrinthine apparatus of the inner ear in response to body
motion.

Peripheral stimuli from visceral organs and vasculature (via vagal and
spinal sympathetic nerves) as a result of exogenous chemicals and
endogenous substances that accumulate during inflammation, ischemia, and
irritation.

The CTZ is located in the area postrema, one of the circumventricular regions
of the brain on the dorsal surface of the medulla oblongata at the caudal end
of the fourth ventricle. Unlike vasculature within the blood-brain diffusion
barrier, the area postrema is highly vascularized with fenestrated blood
vessels, which lack tight junctions (zonae occludentes) between capillary
endothelial cells. The CTZ is anatomically specialized to readily sample
elements present in the circulating blood and cerebrospinal fluid (CSF).[3,4]

Currently, evidence indicates that acute emesis following chemotherapy is
initiated by the release of neurotransmitters from cells that are susceptible
to the presence of toxic substances in the blood or CSF. Area postrema cells
in the CTZ and enterochromaffin cells within the intestinal mucosa are
implicated in initiating and propagating afferent stimuli that ultimately
converge on central structures corresponding to a vomiting center. The
relative contribution from these multiple pathways culminating in N&V symptoms is complex and is postulated to account for the variable
emetogenicity (intrinsic emetogenicity and mitigating factors [i.e., dosage,
administration route, and exposure duration]) and emetogenic profile (i.e., time to
onset, symptom severity, and duration) of agents.

General Risk Factors and Etiologies

Not all cancer patients will experience nausea, vomiting (emesis), or both. The most
common causes are emetogenic chemotherapy drugs and radiation therapy to the
gastrointestinal (GI) tract, liver, or brain. Several patient characteristics have
also been identified. These include the following:

Incidence and severity of nausea and
vomiting (N&V) during past courses of chemotherapy. Patients with poor control of N&V during prior chemotherapy cycles are likely to experience N&V in subsequent cycles.

History of chronic alcohol
use. N&V is less likely in patients with a history of chronic high intake of alcohol.[1]

The psychological variables of state
anxiety (level of anxiety during chemotherapy infusions) and pretreatment
expectations for N&V (self-fulfilling prophecy) have also been
investigated as predictors of posttreatment nausea.[4-9] Studies
have found mixed results that vary because of different research methods. However, better
designed studies have found state anxiety and patient
expectations for nausea to be predictors of posttreatment nausea, even after
controlling for known physiological predictors (susceptibility to nausea during
pregnancy and motion sickness) and emetogenic potential of the chemotherapy
drugs.[6-8,10,11] It is important to note that patients’ fears and
expectations about chemotherapy can be variable and change over time.[12] In a
longitudinal study,[12] patients’ anticipatory fears of vomiting decreased
significantly from pretreatment to a period 3 to 6 months later, particularly
when their chemotherapy included antiemetic medications.

Clinicians treating N&V must be alert to all potential causes and factors,
especially in cancer patients who may be receiving combinations of several
treatments and medications. (Refer to the PDQ summary on Pain for more
information on opioid-induced N&V.)

Anticipatory Nausea and Vomiting (Emesis)

Prevalence

The prevalence of anticipatory nausea and vomiting (emesis) (ANV) has varied, owing to
changing definitions and assessment methods.[1] However, anticipatory nausea
appears to occur in approximately 29% of patients receiving chemotherapy (about one of three patients), while anticipatory vomiting appears to occur in 11% of
patients (about one of ten patients).[2] With the introduction of new pharmacologic agents
(5-hydroxytryptamine-3 or 5-HT3 receptor antagonists), it was anticipated that the prevalence of ANV
might decline; however, studies have shown mixed results. One study found a
lower incidence of ANV,[3] and three studies found comparable incidence
rates.[2,4,5] It appears that the 5-HT3 agents reduce postchemotherapy
vomiting but not postchemotherapy nausea,[2,5] and the resulting impact on ANV
is unclear.

Classical Conditioning

Although other theoretical mechanisms have been proposed,[6] ANV appears to be
best explained by classical conditioning (also known as Pavlovian or respondent
conditioning).[7] In classical conditioning, a previously neutral stimulus
(e.g., smells of the chemotherapy environment) elicits a conditioned
response (e.g., ANV) after a number of prior pairings or learning trials. In
cancer chemotherapy, the first few chemotherapy infusions are the learning
trials. The chemotherapy drugs are the unconditioned stimuli that elicit
postchemotherapy nausea and vomiting (N&V) (in some patients). The drugs are paired with
a variety of other neutral, environmental stimuli (e.g., smells of the setting,
oncology nurse, chemotherapy room). These previously neutral stimuli then
become conditioned stimuli and elicit ANV in future chemotherapy cycles. ANV
is not an indication of psychopathology but is rather a learned response that, in
other life situations (e.g., food poisoning), results in adaptive avoidance.

A
variety of correlational studies provide empirical support for classical
conditioning. For example, the prevalence of ANV prior to any chemotherapy is
very rare, and few patients ever experience ANV without prior postchemotherapy
nausea.[8] Also, most studies have found (1) a higher probability of ANV with
increasing numbers of chemotherapy infusions, and (2) the intensity of ANV
increasing as patients get closer to the actual time of their infusion.[9] In
one experimental study, it was shown that a novel beverage could become a
conditioned stimulus to nausea when paired with several chemotherapy
treatments.[10]

Variables Correlated with ANV

Many variables have been investigated as potential factors that correlate with
the incidence of ANV in hopes of developing a list of risk factors. There is
currently no agreement on which factors predict ANV. A patient with fewer than
three of the first eight characteristics listed below, however, is unlikely to develop ANV, and
screening following the first chemotherapy infusion could identify those
patients at increased risk.[11]

Progressive muscle relaxation
with guided imagery, hypnosis, and systematic desensitization has been studied
the most and is the recommended treatment. Referral to a psychologist or
other mental health professional with specific training and experience in
working with cancer patients is recommended when ANV is identified. The
earlier ANV is identified, the more likely treatment will be effective;
thus, early screening and referral are essential.
However, physicians and nurses underestimate the incidence of chemotherapy-induced nausea and vomiting.[26][Level of evidence: II]

Chemotherapy is the most common treatment-related cause of N&V.
The incidence and severity of acute emesis in persons receiving chemotherapy
varies according to many factors, including the particular drug, dose, schedule
of administration, route, and individual patient variables. In most cancer patients, these symptoms can be prevented or controlled.

Emetic classifications: The American Society of Clinical Oncology has developed a rating system
for chemotherapeutic agents and their respective risk of acute and delayed
emesis.[3]

High risk: Emesis that has been documented to occur in more than 90% of patients:

Cisplatin (Platinol).

Mechlorethamine (Mustargen).

Streptozotocin (Zanosar).

Cyclophosphamide (Cytoxan), 1,500 mg/m2 or more.

Carmustine (BiCNU).

Dacarbazine (DTIC-Dome).

Dactinomycin.

Moderate risk: Emesis that has been documented to occur in 30% to 90% of
patients:

Carboplatin (Paraplatin).

Cyclophosphamide (Cytoxan), less than 1,500 mg/m2.

Daunorubicin (DaunoXome).

Doxorubicin (Adriamycin).

Epirubicin (Pharmorubicin).

Idarubicin (Idamycin).

Oxaliplatin (Eloxatin).

Cytarabine (Cytosar), more than 1 g/m2.

Ifosfamide (Ifex).

Irinotecan (Camptosar).

Low risk: Emesis that has been documented to occur in 10% to 30% of patients:

Mitoxantrone (Novantrone).

Paclitaxel (Taxol).

Docetaxel (Taxotere).

Mitomycin (Mutamycin).

Topotecan (Hycamtin).

Gemcitabine (Gemzar).

Etoposide (Vepesid).

Pemetrexed (Alimta).

Methotrexate (Rheumatrex).

Cytarabine (Cytosar), less than 1,000 mg/m2.

Fluorouracil (Efudex).

Bortezomib (Velcade).

Cetuximab (Erbitux).

Trastuzumab (Herceptin).

Minimal risk: Emesis that has been documented to occur in fewer than 10% of patients:

Vinorelbine (Navelbine).

Bevacizumab (Avastin).

Rituximab (Rituxan).

Bleomycin (Blenoxane).

Vinblastine (Velban).

Vincristine (Oncovin).

Busulphan (Myleran).

Fludarabine (Fludara).

2-Chlorodeoxyadenosine (Leustatin).

In addition to emetogenic potential, the dose and schedule used are also
extremely important factors. For example, a drug with a low emetogenic
potential given in high doses may cause a dramatic increase in the potential to
induce N&V. Standard doses of cytarabine rarely produce N&V, but these are often seen with high doses of this drug. Another
factor to consider is the use of drug combinations. Because most patients
receive combination chemotherapy, the emetogenic potential of all of the drugs
combined and individual drug doses needs to be considered.

Delayed N&V

Delayed (or late) N&V occurs
more than 24 hours after chemotherapy administration. Delayed N&V is associated with
cisplatin, cyclophosphamide, and other drugs (e.g., doxorubicin and ifosfamide)
given at high doses or given on 2 or more consecutive days.

Etiologies:

Patients who experience acute emesis with chemotherapy are significantly more
likely to have delayed emesis.

Risk factors:

All predicative characteristics for acute emesis are considered risk
factors for delayed emesis.

Prevention of Acute/Delayed Nausea and Vomiting (Emesis)

Antiemetic agents are the most common intervention in the management of
treatment-related nausea and vomiting (N&V). The basis for antiemetic therapy is the
neurochemical control of vomiting. Although the exact mechanism is not well
understood, peripheral neuroreceptors and the chemoreceptor trigger zone (CTZ)
are known to contain receptors for serotonin, histamine (H1 and H2), dopamine,
acetylcholine, opioids, and numerous other endogenous neurotransmitters.[1,2]
Many antiemetics act by competitively blocking receptors for these substances,
thereby inhibiting stimulation of peripheral nerves at the CTZ and possibly at
the vomiting center. Most drugs with proven antiemetic activity can be
categorized into one of the following groups:

Although all routes of administration are listed for each
of the following drugs, the intramuscular (IM) route is used only when no
other access is available. IM delivery is painful, is associated
with erratic absorption of drug, and may lead to sterile abscess formation or
fibrosis of the tissues. This is particularly important when more than one or two
doses of a drug are to be given.

Phenothiazines

Phenothiazines act on dopaminergic receptors at the CTZ, possibly at other central nervous system (CNS) centers, and peripherally. With the exception of thioridazine, many
phenothiazines possess antiemetic activity, including chlorpromazine given in
the 10- to 50-mg dose range orally, IM, intravenously (IV), and
rectally (pediatric dose for patients >12 years: 10 mg every 6–8 hours;
for patients <12 years: 5 mg every 6–8 hours); thiethylperazine given in
the 5- to 10-mg dose range orally, IM, and IV; and
perphenazine. The primary consideration in selecting phenothiazines are
differences in their adverse effect profiles, which substantially correlate
with their structural classes. Generally, aliphatic phenothiazines (e.g.,
chlorpromazine, methotrimeprazine) produce sedation and anticholinergic
effects, while piperazines (e.g., prochlorperazine, thiethylperazine,
perphenazine, fluphenazine) are associated with less sedation but greater
incidence of extrapyramidal reactions (EPRs).

Prochlorperazine

Prochlorperazine is perhaps the most frequently (and empirically) used antiemetic and,
in low doses, is generally effective in preventing nausea associated with
radiation therapy and in treating N&V attributed to very low to
moderately emetogenic chemotherapeutic drugs. Prochlorperazine is a phenothiazine and can be
given orally, IM, IV, and rectally. It is usually
given in the 10- to 50-mg dose range (pediatric dose for children who weigh >10 kg or who are >2 years: orally or rectally, 0.4 mg/kg/dose tid–qid; or IM, 0.1–0.15 mg/kg/dose tid–qid, maximum 40 mg/d).
Higher prochlorperazine doses (e.g., 0.2–0.6 mg/kg/dose) are also given
IV for patients receiving chemotherapy with high emetogenic potential.[3];[4][Level of evidence: I]
Phenothiazines may be of particular value in treating patients who experience
delayed N&V (postacute phase symptoms) on cisplatin
regimens.[5][Level of evidence: I]

As with other dopaminergic antagonists, the most common side effects of
prochlorperazine are EPRs (acute dystonias, akathisias,
neuroleptic malignant syndrome [uncommon], and rarely, akinesias and
dyskinesias) and sedation. Marked hypotension may also result if IV
prochlorperazine is administered rapidly at high doses. Administration over at
least 30 minutes appears adequate to prevent hypotensive episodes.[6-8]

Butyrophenones

Droperidol and haloperidol

Droperidol and haloperidol represent another class of dopaminergic (D2 subtype) receptor
antagonists that are structurally and pharmacologically similar to the
phenothiazines. While droperidol is used primarily as an adjunct to anesthesia
induction, haloperidol is indicated as a neuroleptic antipsychotic drug;
however, both agents have some antiemetic activity. Droperidol is
administered IM or IV, typically from 1 to 2.5 mg every
2 to 6 hours, but higher doses (up to 10 mg) have been safely given.[9,10]
Haloperidol is administered IM, IV, or orally,
typically from 1 to 4 mg every 2 to 6 hours.[11] Results of a small, uncontrolled, open-label study showed some efficacy for haloperidol in palliative care patients.[12] Both agents may produce
EPRs, akathisia, hypotension, and sedation.

Dopamine 2 Antagonists

Metoclopramide

Metoclopramide is a substituted benzamide, which, prior to the introduction of serotonin (5-HT3)
receptor antagonists, was considered the most effective single antiemetic agent
against highly emetogenic chemotherapy such as cisplatin. Although
metoclopramide is a competitive antagonist at dopaminergic (D2) receptors, it
is most effective against acute vomiting when given IV at high doses
(e.g., 0.5–3 mg/kg/dose), probably because it is a weak competitive antagonist
(relative to other serotonin antagonists) at 5-HT3 receptors. It may act on
the CTZ and the periphery. Metoclopramide also increases lower esophageal
sphincter pressure and enhances the rate of gastric emptying, which may factor
into its overall antiemetic effect. It can be administered IV at
the U.S. Food and Drug Administration (FDA)–approved dose of 1 to 2 mg/kg every 2 hours (or less frequently) for three
to five doses. Metoclopramide has also been safely given by IV bolus
injection at higher single doses (up to 6 mg/kg) and by continuous IV
infusion, with or without a loading bolus dose, with efficacy comparable to
multiple intermittent dosing schedules.[13-15]

Metoclopramide is associated
with akathisia and dystonic extrapyramidal effects; akathisia is seen more
frequently in patients older than 30 years, and dystonic extrapyramidal effects are seen more
commonly in patients younger than 30 years. Diphenhydramine, benztropine
mesylate, and trihexyphenidyl are commonly used prophylactically or
therapeutically to pharmacologically antagonize EPRs.[7,16] While cogwheeling rigidity, acute dystonia, and tremor are
responsive to anticholinergic medications, akathisia—the subjective sense of
restlessness or inability to sit still—is best treated by the following:

5-HT3 Receptor Antagonists

Four serotonin receptor antagonists—ondansetron, granisetron, dolasetron,
and palonosetron—are available in the United States. Tropisetron, while not approved by the FDA, is available internationally. Agents in this class are thought to
prevent N&V by preventing serotonin, which is released from
enterochromaffin cells in the gastrointestinal (GI) mucosa, from initiating afferent
transmission to the CNS via vagal and spinal sympathetic nerves.[17] The 5-HT3
receptor antagonists may also block serotonin stimulation at the CTZ and other CNS
structures.

Ondansetron

Several studies have demonstrated that ondansetron produces an antiemetic
response that equals or is superior to high doses of metoclopramide, but
ondansetron has a superior toxicity profile compared with dopaminergic antagonist
agents.[18-22][Level of evidence: I][23,24] Ondansetron (0.15 mg/kg) is given IV 15 to 30
minutes prior to chemotherapy and is repeated every 4 hours for two additional
doses. Alternatively, for patients older than 18 years, a large
multicenter study determined that a single 32-mg dose of ondansetron is more
effective in treating cisplatin-induced N&V than a single 8-mg
dose and is as effective as the standard regimen of three doses at 0.15 mg/kg given every 4 hours starting 30 minutes before chemotherapy.[25][Level of evidence: I] A single-center retrospective chart review has reported ondansetron-loading doses of 16 mg/m2 (maximum, 24 mg) IV to be safe in infants, children, and adolescents.[26] However, data reported to the FDA raises concern about QT prolongation and potentially fatal arrhythmias with a single IV dose of 32 mg. Current drug labeling calls for a maximal single IV dose of 16 mg.[27]

Currently, the oral and injectable ondansetron formulations are approved for
use without dosage modification in patients older than 4 years,
including elderly patients and patients with renal insufficiency. Oral ondansetron
is given 3 times daily starting 30 minutes before chemotherapy and continuing
for up to 2 days after chemotherapy is completed. Patients older than 12 years are given 4 mg per dose. Ondansetron is not approved for use in
children younger than 4 years. Ondansetron clearance is diminished in patients
with severe hepatic insufficiency; therefore, such patients receive a
single injectable or oral dose no higher than 8 mg. There is currently no
information available evaluating the safety of repeated daily ondansetron doses
in patients with hepatic insufficiency. Other effective dosing schedules such as a continuous IV infusion
(e.g., 1 mg/h for 24 h) or oral administration have also been
evaluated.[25]

Transient asymptomatic elevations in liver function tests (alanine and aspartate transaminases), which may be related to concurrent
cisplatin administration.

Ondansetron has been etiologically implicated in
a few case studies involving thrombocytopenia, renal insufficiency, and
thrombotic events.[29] In addition, a few case reports have implicated
ondansetron in causing EPRs. However, it is not clear in some cases whether
the events described were in fact EPRs; in other
reports, the evidence is confounded by concurrent use of other agents that are
known to produce EPRs. Nevertheless, the greatest advantage of serotonin
receptor antagonists over dopaminergic receptor antagonists is that they have
fewer adverse effects.
Despite prophylaxis with ondansetron, many patients receiving doxorubicin, cisplatin, or carboplatin will experience acute and delayed-phase N&V.[30][Level of evidence: II] A randomized, double-blind, placebo-controlled trial suggests that the addition of aprepitant, a neurokinin-1 (NK-1) receptor antagonist, may mitigate N&V.[31][Level of evidence: I] The optimal dose of aprepitant may be 125 mg on day 1 followed by 80 mg on days 2 to 5.[32][Level of evidence: I]

Granisetron

Granisetron has demonstrated efficacy in preventing and controlling N&V at a broad range of doses (e.g., 10–80 µg/kg and empirically, 3
mg/dose). In the United States, granisetron injection, transdermal patch, and oral tablets are
approved for initial and repeat prophylaxis for patients receiving emetogenic
chemotherapy, including high-dose cisplatin. Granisetron is pharmacologically
and pharmacokinetically distinct from ondansetron; however, clinically it
appears equally efficacious and equally safe.[33-36][Level of evidence: I] Both granisetron
formulations are given before chemotherapy, as either a single IV dose
of 10 µg/kg (0.01 mg/kg) or 1 mg orally every 12 hours.

Both granisetron formulations and ondansetron injection share the same
indication against highly emetogenic chemotherapy. In contrast, the oral
ondansetron formulation has been approved only for use against N&V associated with moderately emetogenic chemotherapy.

Currently, granisetron injection is approved for use without dosage
modification in patients older than 2 years, including elderly patients and
patients with hepatic and renal insufficiency. Oral granisetron has not yet
been approved for use in pediatric patients.

Dolasetron

Both oral and injection formulations of dolasetron are indicated for the prevention of N&V associated with moderately emetogenic cancer chemotherapy,
including initial and repeat courses. Oral dolasetron may be dosed as 100
mg within 1 hour before chemotherapy. Dolasetron is given IV or orally at 1.8
mg/kg as a single dose approximately 30 minutes before chemotherapy.

The effectiveness of oral dolasetron in the prevention of chemotherapy-induced
nausea and vomiting (CINV) has been proven in a large randomized, double-blind,
comparative trial of 399 patients.[37][Level of evidence: I] Oral dolasetron was administered in the
range of 25 to 200 mg 1 hour prior to chemotherapy. The other study arm
consisted of oral ondansetron (8 mg) administered 1.5 hours before chemotherapy
and every 8 hours after chemotherapy for a total of three doses. Complete response (CR) rates
improved with increasing doses of dolasetron. Both dolasetron 200 mg and
ondansetron had significantly higher CR rates as compared with
dolasetron 25 or 50 mg. (CR was defined as no emetic
episodes and no use of escape antiemetic medications.) Dolasetron injection
has also been proven effective in the prevention of CINV.[38][Level of evidence: I]

Palonosetron

Palonosetron is a 5-HT3 receptor antagonist (second generation) that has antiemetic activity at both central and GI sites. In comparison to the older 5-HT3 receptor antagonists, it has a higher binding affinity to the 5-HT3 receptors, a higher potency, a significantly longer half-life (approximately 40 hours, four to five times longer than that of dolasetron, granisetron, or ondansetron), and an excellent safety profile.[39][Level of evidence: I] A dose-finding study demonstrated that the effective dose was 0.25 mg or higher.[39] In two large studies of patients receiving moderately emetogenic chemotherapy, CR (no emesis, no rescue) was significantly improved in the acute and the delayed period for patients who received 0.25 mg of palonosetron alone compared with either ondansetron or dolasetron alone.[40];[41][Level of evidence: I] Dexamethasone was not given with the 5-HT3 receptor antagonists in these studies, and it is not yet known whether the differences in CR would persist if dexamethasone was used. In another study,[42][Level of evidence: I] 650 patients receiving highly emetogenic chemotherapy (cisplatin ≥60 mg/m2) also received either dexamethasone and one of two doses of palonosetron (0.25 mg or 0.75 mg) or dexamethasone and ondansetron (32 mg). Single-dose palonosetron was as effective as ondansetron in preventing acute CINV with dexamethasone pretreatment; it was significantly more effective than ondansetron throughout the 5-day postchemotherapy period. In an analysis of the patients in the above studies who received repeated cycles of chemotherapy, one author [43] reported that the CR rates for both acute and delayed CINV were maintained with single IV doses of palonosetron without concomitant corticosteroids. These data will require further review.

On the basis of the studies described above, palonosetron was approved by the FDA in July 2003 for the prevention of acute N&V associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy and for the prevention of delayed N&V associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. One randomized, double-blind, phase III trial compared palonosetron plus dexamethasone with granisetron plus dexamethasone for the prevention of CINV in patients receiving highly emetogenic chemotherapy. Palonosetron was equivalent to granisetron in the acute phase (first 24 hours) and better than granisetron in the delayed phase (24–120 hours), with a comparable safety profile for the two treatments.[44][Level of evidence: I] An open-label study was completed in a cohort of patients who had participated in this phase III randomized controlled trial comparing palonosetron to granisetron, with those who initially responded to palonosetron continuing the treatment over repeated cycles of chemotherapy. The investigators reported a good safety profile over time but provided limited data about adverse events. Another limitation of the study was that no more than 25% of patients were receiving palonosetron by cycle 4; the reasons for these withdrawals—whether lack of effect, adverse events, or other issues—were not reported.[45]

Comparison of agents

Studies suggest that there are no major
differences in efficacy or toxicity of the three first-generation 5-HT3 receptor antagonists
(dolasetron, granisetron, and ondansetron) in the treatment of acute CINV. These three agents are equivalent in efficacy and
toxicity when used in appropriate doses.[46];[47-49][Level of evidence: I]
Although these agents have been shown to be effective in the first 24 hours postchemotherapy (acute phase), they have not been demonstrated to be effective in days 2 to 5 postchemotherapy (delayed phase).[30,50,51]

Palonosetron, the second-generation 5-HT3 receptor antagonist, has been approved for the control of delayed emesis for patients receiving moderately emetogenic chemotherapy.[40];[41][Level of evidence: I]

Despite the use of both first-generation and second-generation 5-HT3 receptor antagonists, the control of acute CINV, and especially delayed N&V, is suboptimal, and there is considerable opportunity for improvement with either the addition or substitution of new agents in current regimens.[30][Level of evidence: II];[52][Level of evidence: I][50,51]

Substance P Antagonists (NK-1 Receptor Antagonists)

The initial clinical studies using the NK-1 receptor antagonists [53-55][Level of evidence: I][56] demonstrated that the addition of an NK-1 receptor antagonist (CP-122,721, CJ-11,794, MK-0869 [aprepitant]) to a 5-HT3 receptor antagonist plus dexamethasone prior to cisplatin chemotherapy improved the control of acute emesis compared with a 5-HT3 receptor antagonist plus dexamethasone and improved the control of delayed emesis compared with placebo. In addition, as a single agent, aprepitant (MK-0869) had an effect similar to that of ondansetron on cisplatin-induced acute emesis but was superior in the control of delayed emesis.

Subsequent studies [57,58][Level of evidence: I] showed that the combination of aprepitant and dexamethasone was similar to a 5-HT3 receptor antagonist plus dexamethasone in controlling acute emesis but was inferior in controlling acute emesis compared with triple therapy (aprepitant, 5-HT3 receptor antagonist, and dexamethasone). These studies also confirmed the improvement of delayed emesis with the use of aprepitant compared with placebo. Two studies [32,59][Level of evidence: I] have also shown an improvement in cisplatin-induced delayed emesis with the combination of aprepitant and dexamethasone compared with dexamethasone alone, with the improvement maintained over repeat cycles of cisplatin chemotherapy.

In two randomized, double-blind, parallel, multicenter, controlled studies (520 patients in each study), patients received cisplatin (≥70 mg/m2) and were randomly assigned to receive either standard therapy with a 5-HT3 receptor antagonist (ondansetron) and dexamethasone prechemotherapy and dexamethasone postchemotherapy (days 2–4) or standard therapy plus aprepitant prechemotherapy and on days 2 and 3 postchemotherapy.[31,60][Level of evidence: I] The CR (no emesis, no rescue) of the aprepitant group in both studies was significantly higher in both the acute period (83%–89%) and the delayed period (68%–75%), compared with the CR of the standard therapy group in the acute period (68%–78%) and delayed period (47%–56%). Nausea was improved in the aprepitant group for some, but not all of the various specific measures of nausea.[31] The studies discussed above formed the basis for the approval of aprepitant by the FDA in March 2003. In combination with other antiemetics, aprepitant is indicated for the prevention of acute and delayed N&V associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. An additional study confirmed the efficacy of aprepitant in the delayed period, when it was compared with ondansetron.[61][Level of evidence: I]

All of the initial studies using aprepitant were conducted in patients receiving highly emetogenic chemotherapy such as cisplatin-based chemotherapy regimens. Subsequently, one group [62][Level of evidence: I] presented a study on the use of aprepitant in 862 breast cancer patients receiving moderately emetogenic chemotherapy (e.g., cyclophosphamide, doxorubicin). Two regimens were compared. Because the chemotherapy was moderately emetogenic, steroids were omitted from both arms, as illustrated in Table 2.

There was a significant improvement in CR (no emesis, no rescue) in the 24 hours after chemotherapy in the patients receiving aprepitant; however, there was no significant improvement in CR on days 2 to 5 in the postchemotherapy period when aprepitant alone was compared with ondansetron alone. The overall (days 1–5) CR was significantly improved for the aprepitant-containing regimen, most likely because of the improvement in the first 24 hours. The control of nausea in moderately emetogenic chemotherapy was not improved with the use of aprepitant without steroids on days 2 and 3 postchemotherapy. These results were consistent for multiple cycles of chemotherapy.[63] The role of aprepitant in moderately emetogenic chemotherapy remains undetermined.

One open-label study demonstrated that in the 5 days postchemotherapy, aprepitant in combination with palonosetron and dexamethasone is safe and highly effective in preventing CINV in patients receiving moderately emetogenic chemotherapy.[64][Level of evidence: II] Another study reported that aprepitant combined with ondansetron and dexamethasone provided superior efficacy in the prevention of acute and delayed CINV in a broad range of patients receiving moderately emetogenic chemotherapy (both anthracycline-cyclophosphamide regimens and nonanthracycline-cyclophosphamide regimens).[65] It is not known whether aprepitant is necessary in all moderately emetogenic regimens.

A randomized phase III trial evaluated the use of aprepitant in combination with a 5-HT3 receptor antagonist and dexamethasone in patients with germ cell tumors who were receiving 5-day cisplatin combination chemotherapy.[66] There was a significant reduction in the amount of emesis
and use of rescue medications with the use of aprepitant. This study suggests that aprepitant may be useful in the prevention of CINV in multiday chemotherapy regimens.

Another randomized phase III trial studied the use of aprepitant, granisetron, and dexamethasone for the prevention of CINV in multiple myeloma autologous stem cell transplant patients receiving melphalan. Statistically positive benefit was seen in patients given this regimen, compared with granisetron and dexamethasone alone, without an increase in side effects.[67]

Fosaprepitant dimeglumine, a water-soluble, phosphorylated analog of aprepitant, is rapidly converted to aprepitant after IV administration.[68] Fosaprepitant (115 mg) was approved by the FDA as an alternative to the 125-mg oral aprepitant dose on day 1 of a 3-day regimen. As demonstrated in a randomized, double-blind study of patients receiving cisplatin chemotherapy, single-dose IV fosaprepitant (150 mg) given with ondansetron and dexamethasone was noninferior to the standard 3-day dosing of oral aprepitant in preventing CINV.[69]

Corticosteroids

Steroids are sometimes used as single agents against mildly to moderately
emetogenic chemotherapy but are more often used in antiemetic drug
combinations.[70][Level of evidence: II];[71,72][Level of evidence: I] Their antiemetic mechanism of action is not fully
understood, but they may affect prostaglandin activity in the brain.
Clinically, steroids quantitatively decrease or eliminate episodes of N&V and may improve patients’ mood, thus producing a subjective sense
of well-being or euphoria (although they also can cause depression and
anxiety). In combination with high-dose metoclopramide, steroids may mitigate
adverse effects such as the frequency of diarrheal episodes.

Steroids are often given IV before chemotherapy and may or may not
be repeated. Dosages and administration schedules are selected empirically.
Dexamethasone is often the treatment of choice in treating N&V
in patients receiving radiation to the brain, as it also reduces cerebral
edema. It is administered orally, IM, or IV in the
dose range of 8 mg to 40 mg (pediatric dose: 0.25–0.5 mg/kg).[73-77]
Methylprednisolone is also administered orally, IM, or
IV at doses and schedules that vary from 40 mg to 500 mg every 6 to
12 hours for up to 20 doses.[72,78]

Dexamethasone is also used orally for delayed N&V. Long-term
corticosteroid use, however, is inappropriate and may cause substantial
morbidity, including the following:

Hyperglycemia and exacerbation of preexisting diabetes or
escalation of subclinical diabetes to clinical pathology.

Adrenal suppression
with hypocortisolism.

Lethargy.

Weight gain.

GI irritation.

Insomnia.

Anxiety.

Mood changes.

Psychosis.

A study that examined chemotherapy in a group of patients with ovarian cancer found that short-term use of glucocorticoids as antiemetics had no negative effects on outcomes (e.g., overall survival or efficacy of chemotherapy).[79] As previously shown with metoclopramide,
numerous studies have demonstrated that dexamethasone potentiates the
antiemetic properties of 5-HT3-blocking agents.[80-84] If administered by
IV, dexamethasone may be given over 10 to 15 minutes, since rapid
administration may cause sensations of generalized warmth, pharyngeal tingling
or burning, or acute transient perineal and/or rectal pain.[76,85-87]

Prednisone and adrenocorticotropic hormone (ACTH) given concomitantly with
other active antiemetic agents have also demonstrated efficacy against
N&V caused by cisplatin-containing chemotherapy during the acute phase (within 24 hours
after receiving chemotherapy).[88-90] In a double-blind, randomized study of
metoclopramide and dexamethasone with or without 1 mg of ACTH, patients
receiving ACTH prophylaxis for cisplatin-containing chemotherapy experienced
a significantly decreased incidence and severity of delayed emesis for up to
72 hours after treatment.[90]

Cannabis

The plant Cannabis contains more than 60 different types of cannabinoids, or components that have physiologic activity. The most popular, and perhaps the most psychoactive, is delta-9-tetrahydrocannabinol (delta-9-THC).[91] There are two FDA-approved products for CINV:

Dronabinol (a synthetic delta-9-THC), as prophylaxis for CINV, 5 mg/m2 orally 1 to 3 hours before chemotherapy and every 2 to 4 hours after chemotherapy, for a total of no more than 6 doses per day.

Nabilone, 1 to 2 mg orally twice a day, for CINV that has failed to respond to other antiemetics.

With respect to CINV, Cannabis products probably target cannabinoid-1 (CB-1) and CB-2 receptors, which are in the CNS.[92] Another product, Sativex, a cannabidiol that is a buccal spray, is under investigation.[93,94]

Much of the research on this class of agent was conducted in the late 1970s and 1980s and compared Cannabis to older antiemetic agents that targeted the dopamine receptor, such as prochlorperazine (Compazine) and metoclopramide (Reglan).[91,95-102] This group of studies demonstrated that Cannabis was as effective for moderately emetogenic chemotherapy as dopaminergic antiemetics or was more effective than placebo.[91] Side effects of Cannabis products included euphoria, dizziness, dysphoria, hallucinations, and hypotension.[91] Despite earlier reports of efficacy, in at least one study, patients did not significantly prefer Cannabis agents because of the side effects.[95]

Since the 1990s, research in nausea and vomiting has elucidated newer and more physiologic targets, namely 5-HT3 and NK-1 receptors. Subsequently, 5-HT3 and NK-1 receptor antagonists have become standard prophylactic therapy for CINV. Studies investigating the role of Cannabis with these newer agents are few; therefore, limited conclusions can be drawn. In published trials, however, Cannabis has not demonstrated more efficacy than 5-HT3 receptor antagonists, and synergistic or additive effects have not been fully investigated.[92,103,104]

In summary, the place of Cannabis in today’s arsenal of antiemetics for the prevention and treatment of CINV is not known. Discussions with patients about its use may include responses to available agents, known side effects of Cannabis, and an assessment of the risks versus benefits of this therapy.[105]

Benzodiazepines

Benzodiazepines such as lorazepam, midazolam, and alprazolam have become
recognized as valuable adjuncts in the prevention and treatment of anxiety and
the symptoms of anticipatory nausea and vomiting (ANV) associated with chemotherapy,
especially with the highly emetogenic regimens given to children.[106-108] Benzodiazepines have not demonstrated intrinsic
antiemetic activity as single agents. Therefore, their place in antiemetic
prophylaxis and treatment is adjunctive to other antiemetic agents.[109]
Benzodiazepines presumably act on higher CNS structures, the brainstem, and
spinal cord, and they produce anxiolytic, sedative, and anterograde amnesic
effects. In addition, they markedly decrease the severity of EPRs, especially
akathisia, associated with dopaminergic receptor antagonist antiemetics.

Lorazepam

Lorazepam may be administered orally, IM, IV, and sublingually.
Dosages range from 0.5 to 3 mg (alternatively, 0.025–0.05 mg/kg, or 1.5
mg/m2, but ≤4 mg per dose) in adults and 0.03 to 0.05 mg/kg in
children every 6 to 12 hours.[110][Level of evidence: I][106,111,112] Midazolam produces mild-to-marked
sedation for 1 to 4.5 hours at doses equal to 0.04 mg/kg given IV
over 3 to 5 minutes.[113,114] Alprazolam has been shown to be effective when
given in combination with metoclopramide and methylprednisolone.[115]

Olanzapine

Olanzapine is an antipsychotic in the thienobenzodiazepine drug class that blocks multiple neurotransmitters: dopamine at D1, D2, D3, and D4 brain receptors; serotonin at 5-HT2a, 5-HT2c, 5-HT3, and 5-HT6 receptors; catecholamines at alpha-1 adrenergic receptors; acetylcholine at muscarinic receptors; and histamine at H1 receptors.[117] Common side effects include the following:[118-120]

Sedation.

Dry mouth.

Increased appetite.

Weight gain.

Postural hypotension.

Dizziness.

Olanzapine has also been associated with increased risk of hyperlipidemia, hyperglycemia, new-onset diabetes and, in rare cases, diabetic ketoacidosis.[118,120,121] Olanzapine is used with caution in elderly patients; it has been associated with increased risk of death and increased incidence of cerebrovascular adverse events in patients with dementia-related psychosis and carries a boxed warning to that effect.[118] Olanzapine's activity at multiple receptors, particularly at the D2 and 5-HT3 receptors that appear to be involved in N&V, suggests that it may have significant antiemetic properties.

There have been case reports on the use of olanzapine as an antiemetic.[122][Level of evidence: II];[123-126] These case reports prompted a phase I study in which olanzapine was used for the prevention of delayed emesis in cancer patients receiving their first cycle of chemotherapy consisting of cyclophosphamide, doxorubicin, cisplatin, and/or irinotecan.[127] The protocol was completed by 15 patients, and no grade 4 toxicities were seen. The maximum tolerated dose was 5 mg/day for 2 days prior to chemotherapy and 10 mg/day for 7 days postchemotherapy. On the basis of these data, olanzapine appeared to be a safe and effective agent for the prevention of delayed emesis in chemotherapy-naive cancer patients receiving cyclophosphamide, doxorubicin, cisplatin, and/or irinotecan.

Using the maximum tolerated dose of olanzapine in the phase I trial, a phase II trial was performed for the prevention of CINV in patients receiving their first course of either highly emetogenic or moderately emetogenic chemotherapy. Olanzapine was added to granisetron and dexamethasone prechemotherapy and to dexamethasone postchemotherapy. CR (no emesis, no rescue) was 100% for the acute period (24 hours postchemotherapy), 80% for the delayed period (days 2–5 postchemotherapy), and 80% for the overall period (0–120 hours postchemotherapy) in ten patients receiving highly emetogenic chemotherapy (cisplatin, ≥70 mg/m2). CR was also 100% for the acute period, 85% for the delayed period, and 85% for the overall period in 20 patients receiving moderately emetogenic chemotherapy (doxorubicin, ≥50 mg/m2). Nausea was very well controlled in the patients receiving highly emetogenic chemotherapy, with no patient having nausea (0 on a scale of 0–10, M. D. Anderson Symptom Inventory) in the acute or delayed periods. Nausea was also well controlled in patients receiving moderately emetogenic chemotherapy, with no nausea in 85% of patients in the acute period and in 65% of patients in the delayed and overall periods. There were no grade 3 or 4 toxicities. On the basis of these data, olanzapine appeared to be safe (sedation was the only dose-limiting toxicity) and effective in controlling acute and delayed CINV in patients receiving highly emetogenic and moderately emetogenic chemotherapy.[128][Level of evidence: II]

Subsequent studies have shown the effectiveness of olanzapine as an antiemetic. Olanzapine combined with a single dose of dexamethasone and a single dose of palonosetron was very effective in controlling acute and delayed CINV in patients receiving either moderately emetogenic chemotherapy or highly emetogenic chemotherapy.[129] A large end study [130][Level of evidence: I] demonstrated that in patients receiving either highly emetogenic chemotherapy or moderately emetogenic chemotherapy, the addition of olanzapine to azasetron and dexamethasone improved the CR of delayed CINV.

Other Pharmacologic Agents

Ginger

The antiemetic effect of ginger powder (Zingiber officinale) was explored in a double-blind, placebo-controlled, randomized trial among 32 children and young adults, aged 8 to 21 years, with newly diagnosed bone sarcomas.[131] Cycles of chemotherapy were randomly assigned to ginger powder (1,000 to 2,000 mg per day) or placebo on days 1 to 3 of treatment. Patients were allowed to receive the standard antiemetic medications ondansetron and dexamethasone. The primary endpoint was the incidence and severity of acute N&V (occurring ≤24 hours from the start of chemotherapy) and delayed N&V (occurring >24 hours after completion of chemotherapy).

The authors reported a reduction in the incidence of moderate to severe acute nausea in the experimental arm (55.6% of cycles), compared with the placebo arm (93.3% of cycles) (P = .003). Decreased incidence of moderate to severe vomiting was found in the experimental arm (33.3%), compared with the placebo arm (76.7%) (P = .002). The authors also reported decreased incidence of moderate to severe delayed nausea (P < .001) and vomiting (P = .022) in the experimental arm, compared with placebo. No adverse events were reported.[131]

Although these results are encouraging, the study was limited by a small sample size, lack of stratification by antiemetic regimen, and no intra- or interindividual reporting.

A phase III, randomized, dose-finding trial of 576 patients with cancer evaluated 0.5 g, 1 g, and 1.5 g of ginger versus placebo in twice-a-day dosing for the prevention of acute nausea (defined as day 1 postchemotherapy) in patients experiencing some level of nausea (as measured on an 11-point scale) caused by their current chemotherapy regimen, despite standard prophylaxis with a 5-HT3 receptor antagonist. Patients began taking ginger or placebo capsules 3 days before each chemotherapy treatment and continued them for 6 days. For average nausea, 0.5 g of ginger was significantly better than placebo; both 0.5 g and 1 g were significantly better than placebo for “worst nausea.” Effects for delayed nausea and vomiting were not significant. Emetogenicity of chemotherapy regimens was not controlled for. Adverse events were infrequent and were not severe.[132]

Management of CINV

Current guidelines [133,134] recommend that prechemotherapy management of CINV be based on the emetogenic potential of the chemotherapy agent(s) selected. For patients receiving regimens with high emetogenic potential, the combination of a 5-HT3 receptor antagonist, aprepitant, and dexamethasone is recommended prechemotherapy; lorazepam may also be used. Aprepitant and dexamethasone are recommended postchemotherapy for the prevention of delayed emesis.

For patients receiving moderately emetogenic chemotherapy, the combination of a 5-HT3 receptor antagonist and dexamethasone is used prechemotherapy, with or without lorazepam. Patients receiving the combination of an anthracycline and cyclophosphamide and select patients receiving certain other agents of moderate emetic risk, such as cisplatin (<50 mg/m2) or doxorubicin, may also receive aprepitant. Postchemotherapy, a 5-HT3 receptor antagonist, dexamethasone, or both are recommended for the prevention of delayed emesis.

For regimens with low emetogenic potential, dexamethasone is recommended with or without lorazepam. For regimens with minimal emetogenic risk, no prophylaxis is recommended.[133,134]

Antiemetic guidelines [133,134] have included the available oral 5-HT3 receptor antagonists as optional therapy for the prevention of delayed emesis, but the level of evidence supporting this practice is low.[50]

Studies have strongly suggested that patients experience more acute and delayed CINV than is perceived by practitioners.[50,135,136] One study suggested that patients who are highly expectant of experiencing nausea appear to experience more postchemotherapy nausea.[137] In addition, the current and new agents have been used as prophylaxis for acute and delayed CINV and have not been studied for use in established CINV.[50,51] One study reported the effective use of IV palonosetron and dexamethasone for the prevention of CINV in patients receiving multiple-day chemotherapy.[138]

Pre- and postchemotherapy recommendations by emetogenic potential are summarized in Table 3.

For patients receiving cisplatin and all other agents of high emetic risk, the two-drug combination of dexamethasone and aprepitant recommended for prevention of delayed emesis.

For prevention of delayed emesis, dexamethasone (8 mg) on days 2–4 plus aprepitant (80 mg) on days 2 and 3 recommended, with or without lorazepam on days 2–4.

Moderate (30%–90%) risk

For patients receiving an anthracycline and cyclophosphamide, the three-drug combination of a 5-HT3 receptor antagonist, dexamethasone, and aprepitant recommended prechemotherapy; single-agent aprepitant recommended on days 2 and 3 for prevention of delayed emesis.

For patients receiving an anthracycline and cyclophosphamide and selected patients receiving other chemotherapies of moderate emetic risk (e.g., carboplatin, cisplatin, doxorubicin, epirubicin, ifosfamide, irinotecan, or methotrexate), a 5-HT3 receptor antagonist (ondansetron, granisetron, dolasetron, or palonosetronb), dexamethasone (12 mg), and aprepitant (125 mg) recommended, with or without lorazepam, prechemotherapy; for other patients, aprepitant is not recommended.

For patients receiving other chemotherapies of moderate emetic risk, the two-drug combination of a 5-HT3 receptor antagonist and dexamethasone recommended prechemotherapy; single-agent dexamethasone or a 5-HT3 receptor antagonist recommended on days 2 and 3 for prevention of delayed emesis.

For prevention of delayed emesis, dexamethasone (8 mg) or a 5-HT3 receptor antagonist on days 2–4 or, if used on day 1, aprepitant (80 mg) on days 2 and 3, with or without dexamethasone (8 mg) on days 2–4, recommended, with or without lorazepam on days 2–4.

Metoclopramide, with or without diphenhydramine; dexamethasone (12 mg); or prochlorperazine recommended, with or without lorazepam.

Minimal (<10%) risk

No antiemetic administered routinely pre- or postchemotherapy.

No routine prophylaxis; consider using antiemetics listed under primary prophylaxis as treatment.

Current Clinical Trials

Check NCI’s list of cancer clinical trials for U.S. supportive and palliative care trials about
nausea and vomiting therapy that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Frequency

Nausea and vomiting (N&V) are common symptoms in patients with advanced cancer,
occurring in approximately 21% to 68% of these patients.[1,2] The underlying
pathophysiology and treatment differs somewhat from nausea related to radiation
treatment or chemotherapy. Chronic nausea can significantly impair a patient’s
quality of life.

Pathophysiology and Causes

Chronic nausea in the advanced cancer setting is often multifactorial in
origin.[1-3] Medications, including some that are frequently prescribed in this
setting—such as opioids, nonsteroidal anti-inflammatory
drugs, and selective serotonin reuptake inhibitor antidepressants—may be
responsible.

In the case of opioids, nausea frequently resolves spontaneously
a few days after initiation of treatment. In some cases, however, it may
persist. Nausea resulting from the accumulation of active opioid metabolites
(morphine-6-glucuronide) has been described,[4] and patients with impaired
renal function may be at increased risk. Opioids invariably produce
constipation if prophylactic measures are not taken (namely, the use of a
regular laxative regimen), and constipation is one of the most common causes of
nausea in patients with advanced cancer.[5-8]

Opioid-induced gastrointestinal (GI)
motility problems may compound the problem of diminished GI
motility that many patients experience as part of the anorexia-cachexia
syndrome of advanced cancer. The autonomic dysfunction that often accompanies
this syndrome results in decreased GI motility, early satiety,
and chronic nausea.[9-11] Other causes of chronic nausea in these patients
include the following:[12]

Metabolic abnormalities such as hypercalcemia, hyponatremia, and
uremia.

Dehydration.

Malignant bowel obstruction.

Gastroduodenal ulcers.

Infections of the mouth, pharynx, or esophagus.

Nausea, like many other symptoms, may have psychological undercurrents that
either exacerbate or induce chronic nausea.

Assessment

A comprehensive history that includes determining the frequency and
effectiveness of bowel movements and laxative therapy is essential. Concurrent
medications are reviewed, and the frequency and nature of N&V is documented. Examination will assess for bowel obstruction, fecal impaction, dehydration, and raised
intracranial pressure. History and physical examination are poor at
determining the extent of constipation.[5] A plain flat-plate x-ray of the
abdomen can be very useful to this end.[13] Surgical x-ray views of the
abdomen may be helpful if a bowel obstruction is suspected. Investigations to
determine blood levels of electrolytes, calcium, and renal parameters may also
be helpful.

Management

Management centers on identifying the underlying causes, addressing these when
possible, and controlling the symptoms.[1,2] A basic working knowledge of the
emetic pathways and identification of possible underlying causes guide
antiemetic selection.

Multiple antiemetic regimens have been proposed for the
management of chronic nausea in the advanced cancer setting. Prospective
studies comparing one regimen with another are lacking. Metoclopramide or
domperidone are generally recommended as first-line agents because they improve
GI motility and act on the chemoreceptor trigger zone (as a
result of their antidopaminergic properties).[14] Metoclopramide can be
administered orally or parenterally (subcutaneously or intravenously [IV]) at doses
of 10 mg, 4 times a day, or on an every-4-hour basis, depending on the severity of
the nausea. Rescue doses are ordered on an as-needed basis to
manage the episodic worsening of nausea that may occur.

Extrapyramidal-related
adverse effects are a potential complication of these medications but appear
to occur infrequently. Domperidone, which is currently unavailable in the
United States, is associated with fewer of these adverse effects.
Unfortunately, this drug is not available in a parenteral formulation.
Dimenhydrinate (Dramamine) or antihistamine agents may be used if a complete
bowel obstruction is suspected (in which case prokinetic agents are
contraindicated) or if patients are intolerant to other antiemetic agents.
Haloperidol, a potent antidopamine agent, may be considered if bowel
obstruction is the underlying problem.[15]

The phenothiazine drugs are
sometimes used,[16][Level of evidence: II] but the high incidence of adverse effects such as somnolence
and anticholinergic-related effects (orthostatic hypotension and confusion)
limit their role. Chlorpromazine has modest antiemetic activity but a high
incidence of sedation, postural hypotension, and anticholinergic adverse
effects, while piperazine derivatives such as prochlorperazine are stronger
antiemetics but cause more extrapyramidal side effects. Hyoscine butylbromide,
on the other hand, can be useful for patients experiencing colic from complete
bowel obstruction.

A continuous parenteral infusion of metoclopramide, at doses of 60 to 120 mg/day, may be helpful for patients with intractable chronic nausea.[17] The
judicious use of corticosteroids such as dexamethasone in selected patients may be useful in conjunction with a more traditional antiemetic, although one study has suggested that dexamethasone was not better than placebo in patients who were not controlled with metoclopramide.[18][Level of evidence: I] The
exact mechanism of action and the optimal dose of corticosteroids for this
indication are not known.

In contrast to radiation therapy–induced nausea or chemotherapy-induced nausea, the role of
5-HT3 receptor antagonists (such as ondansetron) is not clear in the setting of
chronic nausea in advanced cancer, but it appears to be limited to a small number
of highly selected cases, specifically those that have failed all other
treatments.[19]

A case series study has suggested an antiemetic effect for olanzapine (an atypical antipsychotic) in advanced cancer patients being treated with opioids who are complaining of apparent opiate-induced nausea. However, further study and comparison with standard management are required.[20]

The management of constipation can be divided into general interventions and
therapeutic measures.[21] The general interventions include the prevention of
constipation by initiating regular laxative regimens, particularly in patients
on opioid treatment, and where possible, the elimination of medical factors
that may be contributing to constipation (e.g., discontinuation of nonessential
constipating drugs). Prophylactic laxative regimens may consist of stool
softeners such as docusate and bowel stimulants such as sennosides.
Occasionally lactulose may be added. If necessary, a hyperosmolar laxative such as lactulose or polyethylene glycol may be added.[22] These regimens are reviewed on a
regular basis and their doses adjusted, depending on the regularity of bowel
movements. High-fiber diets, while generally recommended, may be difficult for
patients with very advanced cancer. Bulk agents such as psyllium or cellulose
are unsuitable for patients with advanced cancer because the high fluid intake
required with these agents is often intolerable to patients.
(Refer to the PDQ summaries on Gastrointestinal Complications and Pain for more information on the management of constipation caused by opioids.)

Therapeutic interventions for the routine management of constipation may be
administered orally or rectally, as follows:

Saline laxatives,
including sodium salts (sodium phosphate) and magnesium salts (magnesium
citrate), may be useful to treat established constipation.

Sodium phosphates
are generally administered rectally as an enema, but oral solutions are also
available.

Magnesium citrate is generally administered orally and can be
especially useful if the constipation is primarily in the proximal bowel.

The
contact cathartic bisacodyl, available as a suppository, may also be useful for
treating established constipation.

Once the constipation is cleared, the
background laxative regimen (e.g., sennoside and docusate) is reviewed
with a view to optimizing it. The action of the saline and magnesium salts
is not physiological, and regular ongoing administration is avoided.
Saline laxatives are used with caution in patients with renal impairment
or cardiac failure. Mineral oil enemas are used occasionally and act as both
lubricants and stool softeners; however, they may interfere with the absorption of
fat-soluble vitamins, and there is a risk of lipoid pneumonia in
debilitated patients. The use of enemas and rectal suppositories is usually
limited to the acute short-term management of more severe episodes of
constipation. However, patients with neurogenic bowel problems (e.g., patients with
irreversible spinal cord compression) often require regular ongoing
treatment with suppositories as part of their bowel care. The rectal route is
contraindicated in patients with mucosal integrity/bowel-wall compromise.
(Refer to the PDQ summary on Gastrointestinal Complications for more information.)

There have been no adequate comparative studies between the
various laxatives to make evidence-based recommendations on which laxative
regimen is optimal. Patients with advanced cancer are at risk of becoming
constipated and generally require a regular bowel regimen, even if they are not
eating. This need is amplified when they are on opioid treatment. On occasion,
patients may present with a refractory narcotic bowel syndrome despite
aggressive bowel care. Methylnaltrexone, a quaternary derivative of naltrexone, is an opioid antagonist that does not cross the blood-brain barrier. Preliminary studies suggest that it may be effective when given subcutaneously in the management of opioid-associated constipation without causing opioid withdrawal.[23][Level of evidence: I];[24,25] Methylnaltrexone is avoided in cases of bowel obstruction and suspected bowel obstruction. This has not been studied in children.

Malignant Bowel Obstruction

The initial approach to assessing and managing malignant bowel obstruction in
the advanced cancer patient involves determining whether the obstruction is
reversible and whether the obstruction is partial or complete.[26-28]
Suitability for surgery such as resection or intestinal bypassing is
assessed. Several medical options are available to improve the comfort of
patients with inoperable bowel obstructions.[29,30] Less aggressive surgical
procedures such as the insertion of a venting gastrostomy tube can provide
considerable relief. When the obstruction is
complete and irreversible, the creation of ostomies may also provide relief. Nasogastric tubes may be
used temporarily until the obstruction resolves; however, when the obstruction is
irreversible, other options such as the insertion of a gastrostomy tube are considered.

Antiemetic agents with prokinetic properties are relatively
contraindicated in the presence of a complete obstruction, and alternative
agents such as an antihistamine or haloperidol may be required. Clinical
experience suggests that corticosteroids (e.g., dexamethasone at a starting
dose of 6–10 mg subcutaneously, 3–4 times a day) may be useful for malignant
bowel obstruction.[26,27] The optimal dose and duration of treatment has not
been clarified.

Hydration and drugs such as opioids and antiemetics are
administered via routes other than the oral route. The subcutaneous route can
be very convenient and effective for both hydration and opioid administration.
This route is as effective as IV administration, is less invasive, and
requires less maintenance than the IV route. Octreotide, a somatostatin
analog, can be useful at doses of 100 µg to 200 µg subcutaneously, 3 times
a day, for refractory obstruction.[26,27,31] In the United States, octreotide is often
administered as a continuous infusion. If the obstruction causes severe colic,
hyoscine butylbromide may be considered. The use of colonic endoluminal
stenting devices in selected patients is gaining increasing attention.[32,33]

Acupuncture. (Refer to the PDQ summary on Acupuncture for more information.)

Acupressure.

Relaxation techniques.

Behavioral therapy.

Guided imagery.

Guided imagery, hypnosis, and systematic desensitization as means to progressive muscle relaxation have been the most frequently studied treatments for anticipatory nausea and vomiting (ANV) and are the recommended treatments for this classically conditioned response. (Refer to the Treatment of ANV section of this summary for more information.)

Radiation Therapy

Correlates

Patients receiving radiation to the gastrointestinal (GI) tract or brain have the greatest
potential for nausea and vomiting (N&V) as side effects. Because cells of the GI tract
are dividing quickly, they are quite sensitive to radiation therapy. Radiation
to the brain is believed to stimulate the brain’s vomiting center or chemoreceptor trigger zone. Similar to chemotherapy, radiation dose factors
also play a role in determining the possible occurrence of N&V.
In general, the higher the daily fractional dose and the greater the amount of
tissue that is irradiated, the higher the potential for N&V.
In addition, the larger the amount of GI tract irradiated (particularly for
fields that include the small intestine and stomach), the higher the potential
for N&V. Total-body irradiation before bone marrow transplant,
for example, has a high probability of inducing N&V as acute
side effects.

Prevalence

N&V from radiation may be acute and self-limiting, usually
occurring 30 minutes to several hours after treatment. Patients report that
symptoms improve on days that they are not being treated. There are also
cumulative effects that may occur in patients receiving radiation therapy to
the GI tract.[1]

Treatment

Complete control rates with 5-HT3 receptor antagonists for total-body irradiation vary
from 50% to 90%.[2-4] The role of corticosteroids in combination with 5-HT3
receptor antagonists has not been studied.

Added text to state that another randomized phase III trial studied the use of aprepitant, granisetron, and dexamethasone for the prevention of chemotherapy-induced nausea and vomiting in multiple myeloma autologous stem cell transplant patients receiving melphalan, and that statistically positive benefit was seen in patients given this regimen, compared with granisetron and dexamethasone alone, without an increase in side effects (cited Schmitt et al. as reference 67).

Questions or Comments About This Summary

If you have questions or comments about this summary, please send them to Cancer.gov through the Web site’s Contact Form. We can respond only to email messages written in English.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of nausea and vomiting (emesis) (N&V). It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,

be cited with text, or

replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Supportive and Palliative Care Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Contact Us

More information about contacting us or receiving help with the Cancer.gov Web site can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the Web site’s Contact Form.

Get More Information From NCI

Call 1-800-4-CANCER

For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.

Chat online

The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 8:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.

Write to us

For more information from the NCI, please write to this address:

NCI Public Inquiries Office

9609 Medical Center Dr.

Room 2E532 MSC 9760

Bethesda, MD 20892-9760

Search the NCI Web site

The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).